Family, twin and adoption studies indicate genetic vulnerability to psychiatric disorders, including antisocial personality (Crowe, Arch. Gen. Psychiatry 31:785, 1974), suicidal behavior (Roy et al., Arch. Gen. Psychiatry 48:29, 1991), panic disorder and anxiety. Family and population studies have shown that these disorders usually co-occur with alcoholism and alcohol abuse (Roy et al., Prog. Neuro-Psychopharmacol. Psychiatry 11:173, 1987). Although psychiatric disorders often arise from a complex combination of environmental, genetic and biological factors, it may be possible to find biochemical and genetic variables that predict these behaviors and also facilitate implementation of preventative and therapeutic measures.
Several lines of evidence suggest that a lower activity of brain serotonergic pathways is related to several neuropsychiatric disorders. For example, lower levels of 5-hydroxyindoleacetic (5-HIAA), the main metabolite of serotonin (5-HT) in the cerebrospinal fluid (CSF) has been reported in clinical studies of aggression, depression, impulsive crime and alcoholism. In the genetic hypothesis of these disorders, vulnerability is transmitted through inheritance of a functionally divergent allele. Variation in central serotonin function would have pleiotropic effects beyond behavior. For example, some effects would be increasing the vulnerability to anxiety and mood disorders as well as impulsive/aggressive behaviors.
Several important genes for normal brain serotonin function have been cloned, including tryptophan hydroxylase (Stoll and Goldman, J. Neurosci. Res. 28:457, 1991), serotonin transporter (Hoffman et al., Science 254:579, 1991) monoamine oxidases A and B (Bach et al., Proc. Natl. Acad. Sci. USA 85:4934, 1988) and several serotonin receptors (Humphrey et al., Trends Pharmacol. Sci. 14:233, 1993).
Serotonin acts in vivobybinding to specific receptors located in the central nervous system. A vast array of serotonin receptors has already been discovered. Investigators have divided the serotonin receptor subtypes into four pharmacologically distinct classes designated 5-HT.sub.1 to 5-HT.sub.4. The 5HT.sub.1 subcategory contains five different subtypes referred to as 5HT.sub.1A-E. The 5-HT.sub.2 receptors can be divided into three subclasses, 5-HT.sub.2A, 5-HT.sub.2B and 5-HT.sub.2C . The primary structures for a number of these receptors have been elucidated by molecular cloning, including the 5-HT.sub.1, 5-HT.sub.2 and 5HT.sub.3 subclasses.
Serotonin receptor agonist and antagonists have been developed as drugs for treating specific neuropsychiatric disorders. Drugs with affinity for 5-HT.sub.2 receptors are used to treat schizophrenia, Parkinsonism, and anxiety disorders. Several azapirones, such as buspirone, gepirone, and ipsapirone, have high affinities for 5HT.sub.1A receptors in the brain, and are used to treat anxiety. For example, clozapine which is an antipsychotic drug with fewer extrapyramidal side effects is used to treat schizophrenic patients who do not respond to other drug treatments. Clozapine has a strong affinity for the serotonin 5-HT.sub.2 subclass of receptors. In addition, 5-HT.sub.1A class agonists, such as buspirone, are effective treatments for anxiety.
Highly selective 5-HT uptake inhibitors, which have minimal effects on norepinephrine or dopamine uptake or on other neurotransmitter receptors, have been used successfully to treat depression. Naturally, characterizing all of the specific 5-HT receptors would clarify the role of serotonin in the central nervous system, and assist neuropsychiatric drug development.
The 5-HT.sub.2C serotonin receptor subtype has been particularly interesting to investigators searching for the molecular bases of neuropsychiatric disorders. The 5-HT.sub.2C receptor gene is widely expressed in the brain where it is involved in regulating endocrine responses. Particular responses include the production and secretion of adrenocorticotropic hormone (ACTH), oxytocin and prolactin. Genes for rat, mouse and human (Saltzman et al., Biochem. Biophys. Res. Commun. 181:1469, 1991) 5-HT.sub.2C receptors have been cloned. The functional state of 5-HT.sub.2C receptors in normal controls and various patient groups has been studied in vivo by administering mCPP, a non-selective 5-HT.sub.2C agonist, and measuring hormonal and psychological responses. In alcoholism, panic disorder, seasonal affective disorder and obsessive-compulsive disorder, mCPP has been shown to induce different hormonal and psychological responses in patients and controls.
As discussed, several lines of evidence suggest abnormal function of serotonin receptors in certain neuropsychiatric disorders. Specifically, pharmacological studies in humans suggest that abnormal function of 5-HT.sub.2C receptors play a role in the etiology of certain disorders. Accordingly, there is a need to identify and characterize the serotonin receptors and those functional variants which associate with neuropsychiatric disorders. There is a corresponding need for assays that will permit identification of functional variants in various segments of the population. With this knowledge, receptor variant-specific drugs and diagnostic information can be developed.